It is known that (-)-Epigallocatechin-3-gallate (EGCG) is the inhibitor of TLR4 signaling pathway activation. To investigate a possible role of TLR4 signaling pathway in the development of atherosclerosis, the effects of EGCG on the development of atherosclerosis, the expression of TLR4 and inflammatory cytokine production in apoE^-/- mice was investigated. Fifty male apoE^-/- mice (5wk old) were divided into four groups: basic diet group (control group), high-fat diet group (control group), EGCG+ basic diet group (EGCG group), and high-fat diet + EGCG group (EGCG group). EGCG (10 mg/kg) was injected intraperitoneally every day. Areas of aortic plaque areas were measured by oil red O staining. Western blot was used to detect the expression of TLR4 and CD14 in mouse aorta. The expression of TLR4 mRNA and CD14 mRNA were detected by Real-time PCR. Serum concentrations of MCP-1 and TNF-α were determined with ELISA. Compared with high-fat diet group, EGCG groups showed marked decreases in aortic atherosclerosis(P < 0.05), concomitantly with significant decreases in levels of the expression of TLR4, TNF-α and MCP-1. The mean lesion area was (2.37 ± 0.08) mm² in the high-fat diet + EGCG group, whereas the atherosclerotic lesion was only (1.05 ± 0.13) mm² in the high-fat diet + EGCG group. The TLR4 expression was obviously higher in high-fat diet group than that in other groups (P < 0.05). Compared with high-diet group, the serum concentrations of MCP-1 and TNF-α were significantly decreased in EGCG groups (P < 0.05). These results suggest that TLR4 signaling pathway may play an important role in the development of atherosclerosis in apoE^-/- mice induced by high-fat diet.